Process for the preparation of halogenated hydroxydiphenyl compounds

ABSTRACT

There is described a process for the preparation of halogenated hydroxydiphenyl compounds of formula (1) by acylation of a halogenated benzene compound (first stage), etherification of the acylated compound with a halogenated phenol compound, which is not further substituted in the ortho-position (second stage), oxidation of the etherified compound (third stage) and hydrolysis of the oxidized compound in a fourth stage, wherein the reaction of the second stage is carried out in the presence of K 2 CO 3  and any desired copper catalyst, where K 2 CO 3  is used in a concentration of from 0.5 to 30 mol, based on the phenol compound employed of formula (6), according to the reaction scheme (I) in which R 1  and R 2  independently of one another are F, Cl or Br; R 3  and R 4  independently of one another are hydrogen; or C 1 -C 4 alkyl; m is 1 to 3; and n is 1 or 2. The compounds of formula (1) are used for protecting organic materials and articles from microorganisms.

This application is a 371 of PCT/EP01/04210, filed Apr. 26, 2001.

The present invention relates to the preparation of halogenatedhydroxydiphenyl compounds of the formula

in which

R₁ and R₂ independently of one another are F, Cl or Br;

R₃ and R₄ independently of one another are hydrogen; or C₁-C₄alkyl;

m is 1 to 3; and

n is 1 or 2;

and to the use of these compounds as disinfectants for protectingorganic materials from microorganisms.

WO 99/10310 discloses a four-stage process for the preparation of2,4,4′-trichloro-2′-hydroxydiphenyl ether (triclosan) by acylation of ahalobenzene compound (first stage), etherification of the acylatedcompound using a halogenated phenol compound in an Ullmann-analogousreaction (second stage), Baeyer-Villiger oxidation of the etherifiedcompound (third stage) and subsequent hydrolysis.

However, the yields in this process are moderate, in particular yieldsof <50% are achieved in the 2^(nd) reaction stage (Ullmanncondensation).

Surprisingly, it has been found that significantly higher yields can beachieved for the second reaction stage if halogenated phenol compoundswhich are not further substituted in the ortho position are used asstarting compounds for the Ullmann condensation.

The present invention therefore relates to a four-stage process for thepreparation of halogenated hydroxydiphenyl compounds, which are notfurther substituted in the 2′- and 6′-position, of the formula (1), inwhich in the first stage a halogenated benzene compound is acylated, inthe second stage the acylated compound is etherified using a halogenatedphenol compound which is not further substituted in the ortho-position,in a third stage the etherified compound is oxidized and in the fourthstage the oxidized compound is hydrolysed, wherein the reaction of thesecond stage is carried out in the presence of K₂CO₃ and any desiredcopper catalyst, where K₂CO₃ is used in a concentration of from 0.5 to 3mol, based on the phenol compound employed of the formula (6), accordingto the following reaction scheme:

In the above scheme, R₁, R₂, R₃, R₄, m and n are as indicated in formula(1).

In the first reaction step (acylation reaction), compounds of theformula (5) are prepared. Usually, this reaction is carried out in thepresence of a Lewis acid, e.g. aluminium halide, in particular aluminiumchloride. The Lewis acid is in this case employed in a 1 to 3,preferably 1.25 to 2, molar amount, based on the halogenated compound ofthe formula (5). A possible acylating reagent for this reaction is anacyl halide, in particular acetyl chloride.

C₁-C₄alkyl is preferably a straight-chain or branched alkyl radical,e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl ortert-butyl.

The Lewis acid and acylating reagent are preferably employed inequimolar amounts. The reaction is carried out in the solvents customaryfor Friedel-Crafts reactions, e.g. nitrobenzene, dichlorobenzene,methylene chloride or ethylene chloride. The reaction time for thisreaction stage plays a minor part and can vary within wide bounds, from,for example, 1 to 18 hours.

In the second reaction stage, the compounds of the formula (7) areprepared. The etherification of the free OH group of the halogenatedphenol compound of the formula (6) is carried out in alkaline mediumusing K₂CO₃, and in the presence of any copper catalyst, for examplemetallic copper, copper(I) and copper(II) oxides, copper halides andcopper acetates or CuCO₃×Cu(OH)₂ and an inert organic solvent, e.g.toluene or a xylene isomer mixture. The reaction can also be carriedout, however, in the presence of polar solvents, for example DMF orDMSO.

The reaction times for this reaction step are usually 1 to 24 hours,preferably 2 to 10 hours; the temperature ranges from 80 to 250° C.,preferably 100 to 170° C.

The base (K₂CO₃) is used in concentrations of preferably from 0.8 to 2mol per mole and very particularly 0.9 to 1.1 mol per mole, based on thephenol compound employed.

The phenol compound of the formula (6) is preferably employed in adefinite excess.

In the third reaction stage (oxidation), compounds of the formula (8)are prepared.

The oxidation of the acyl compound of the formula (7) to the compound ofthe formula (8) (Baeyer-Villiger oxidation) can be carried out usingvarious oxidizing agents. Suitable oxidizing agents are, for example:

a mixture of dilute peracetic acid and acetic anhydride in the presenceof a catalytic amount of perchloric acid;

m-chloroperbenzoic acid (MCPBA) in water;

diperoxydodecanedioic acid (DPDDA);

a mixture of dilute peracetic acid and acetic anhydride and sulfuricacid;

perbenzoic acid (PBA)

a mixture of sodium borate and trifluoroacetic acid;

a mixture of formic acid, hydrogen peroxide, acetic anhydride,phosphorus pentoxide and acetic acid;

a mixture of acetic acid, hydrogen peroxide, acetic anhydride andphosphorus pentoxide;

a mixture of hydrogen peroxide/sulfuric acid/acetic acid;

a mixture of K₂S₂O₈, sulfuric acid and a 1:1 water/methanol mixture;

a mixture of acetic acid and the potassium salt of monoperoxymaleicacid;

a mixture of trichloromethylene, the potassium salt of monoperoxymaleicacid and sodium hydrogen sulfate;

a mixture of maleic anhydride, acetic anhydride, hydrogen peroxide andtrichloromethane;

a mixture of maleic anhydride, a urea-hydrogen peroxide complex andacetic acid;

magnesium monoperphthalate;

a mixture of acetic anhydride, sulfuric acid and H₂O₂;

a mixture of dichloroacetic acid and H₂O₂.

m-Chloroperbenzoic acid (MCPBA) or a mixture of hydrogenperoxide/sulfuric acid/acetic acid is preferably used for the oxidation.

If desired, a commercially available wetting agent can additionally beadded to the oxidizing agent. The reaction times lie in a wide range andrange from about 0.5 to about 15 hours, preferably 1 to 8 hours. Thereaction temperature ranges from −20 to about 100° C., preferably from 0to about 85° C.

The subsequent hydrolysis to give the desired halohydroxydiphenyl etherof the formula (1) proceeds quantitatively in the acidic or alkalinemedium.

The process according to the invention preferably relates to thepreparation of halohydroxydiphenyl compounds of the formula (1), inwhich

R₁ and R₂ are Cl.

Very particularly preferred compounds of the formula (1) have theformula

The halogenated hydroxydiphenyl compounds prepared according to theinvention are insoluble in water, but soluble in dilute sodium hydroxideand potassium hydroxide solution and in virtually all organic solvents.Owing to these solubility requirements, their applicability for thecontrol of microorganisms, in particular of bacteria, and asdisinfectants for protecting organic materials and articles from attackby microorganisms is very versatile. Thus they can be applied to thesein diluted or undiluted form, for example, together with wetting ordispersing agents, e.g. as soap or syndet solutions for the disinfectionand cleaning of human skin and hands, of hard articles and in dentalhygiene compositions.

The following examples illustrate the invention without restricting itthereto.

PREPARATION EXAMPLES Example 1 Preparation of 2,5-dichloroacetophenone(First Reaction Stage)

Reaction Scheme:

147 g (1.0 mol) of p-dichlorobenzene are completely melted at 60° C. inan apparatus having an attached dropping funnel, stirrer and refluxcondenser. 120 g (0.9 mol) of anhydrous AlCl₃ are added to the melt.39.3 g (0.5 mol) of acetyl chloride are then added dropwise to thereadily stirrable suspension at 60° C. in the course of about 1 hour, aclear solution slowly resulting. After heating to 110° C., the mixtureis stirred at this temperature for 7 hours. After cooling to roomtemperature, the brown reaction mass is hydrolysed by cautiousdecantation onto a mixture of 200 ml of water and 200 g of ice. Thetemperature of the mixture is kept between 30 and 40° C. during thehydrolysis by external cooling. After separation of the phases, thelower, organic phase is washed with 400 ml of water and, after freshphase separation, subjected to fractional distillation. The aqueousphases are discarded.

Yield: 66 g of 2,5-dichloroacetophenone (70% of theory, based on acetylchloride)

Example 2 Preparation of1-(5-chloro-2-(2,4-dichlorophenyl)phenylethanone (Second Reaction Stage)

Reaction Scheme:

164.4 g of K₂CO₃ (1.03 mol), 0.86 g of copper(II) oxide and 600 g ofxylene isomer mixture are initially introduced and 132.5 g of4-chlorophenol and 189.1 g of 2,5-dichloro-acetophenone are introducedwith stirring. The grey suspension is heated to reflux at 144° C. and 8g of water are distilled off in a water separator. After a residencetime of 2.5 h at 145° C., the reaction mass is cooled to 80° C., 500 gof water are added and the mixture is stirred for 15 min. Phaseseparation is then awaited in a separating funnel. The lower aqueousphase is separated off (670 g). The conversion in the remaining organicphase (desalted reaction mass; 921 g) is determined by means of HPLC.

Yield: 257.0 g of the compound of the formula (102) (91.3% of theory).

Example 3 Preparation of1-(5-chloro-2-(2,4-dichlorophenoxy)phenyl)ethanone (2nd Reaction Stage)Using Basic Copper Carbonate as the Catalyst

The procedure is as described in Example 2, with the difference thatinstead of copper(II) oxide, basic copper carbonate (CuCO₃×Cu(OH)₂) isemployed. The yield is 260.7 g of the compound of the formula (102);(92.6% of theory).

Example 4 Preparation of 5-chloro-2-(4-chlorophenoxy)phenol (Third andFourth Reaction Stage)

Reaction Scheme:

14 g of the acetyl compound of the formula (102) are suspended in 100 mlof deionized water at 20° C. using a wetting agent. 29 g of 70%3-chloroperbenzoic acid (MCPBA) are scattered in and the mixture isheated with stirring. A resin/water phase is formed from 52° C.; themixture is heated to about 80° C. and kept at this temperature for 7hours.

It is treated with 0.5 g of sodium hydrogen sulfite to destroy excessperoxide. Two clear phases are obtained by addition of 50 ml of xyleneisomer mixture and 9 g of 10N NaOH. The water phase having a pH of about12 is separated off; the solvent phase comprising the compound of theformula (103) is washed with water until neutral.

To hydrolyse the ester, the xylene phase is treated with 24 g of 10%NaOH and stirred under reflux (about 95° C.) for 5 hours. The xylenephase is then separated off and the pale brown water phase is adjustedto a pH of about 3 using 4 g of 34% hydrochloric acid at 25° C. In thecourse of this, the product precipitates in sandy, beige-coloured formand, after filtration, can be thoroughly washed with water on thesuction filter. After drying, 5 g of the crude product of the formula(104) having a melting point of 73 to 74° C. are obtained.

After recrystallization from petroleum ether 80/110, the pure substanceis obtained in colourless crystals having a melting point of 74 to 74.5°C.

Example 5 Preparation of 5-chloro-2-(4-chlorophenoxy)phenol (Third andFourth Reaction Stage)

a) Preparation of the Baeyer-Villiger Reaction (=BV Reagent)

300 g of anhydrous acetic acid are initially introduced, 102 g of 96%sulfuric acid are metered in (internal temperature <30° C.).

106.2 g of 50% hydrogen peroxide solution are metered in, the internaltemperature being maintained at <20° C.

The mixture is then stirred for a further hour at 20° C.

b) Preparation of the Baeyer-Villiger Initial Mixture (=BV InitialMixture)

450 g of anhydrous acetic acid are initially introduced with cooling,440 g of 96% sulfuric acid are metered in (internal temperature <30°C.), 281.1 g of crystalline 2-acetyl-4,4′-dichlorophenyl ether areintroduced at an internal temperature of 20° C.

c) Baeyer-Villiger Reaction

BV reagent is metered into the BV initial mixture in the course of 4hours (internal temperature 30° C.).

The reaction is then kept at an internal temperature of 40° C. for 2hours and at an internal temperature of 50° C. for 0.5 hours.

d) Work-Up

The work-up is carried out according to the customary methods.

623 g of 2-OH-4,4′-DCDPE are obtained as a 30% solution in 1,2-PG. Thiscorresponds to 187 g of 100% strength of 2-OH-4,4′-DCDPE (73% oftheory).

What is claimed is:
 1. A process for the preparation of halogenatedhydroxydiphenyl compounds, which are not substituted in the 2′- and6′-position, of the formula

by acylation of a halogenated benzene compound (first stage),etherification of the acylated compound with a halogenated phenolcompound which is not further substituted in the ortho-position (secondstage), oxidation of the etherified compound (third stage) andhydrolysis of the oxidized compound in a fourth stage, wherein thereaction of the second stage is carried out in the presence of K₂CO₃ andany desired copper catalyst, where K₂CO₃ is used in a concentration offrom 0.5 to 3 mol, based on the phenol compound employed of the formula(6) according to the following reaction scheme:

where R₁ and R₂ independently of one another are F, Cl or Br; R₃ and R₄independently of one another are hydrogen; or C₁-C₄alkyl; m is 1 to 3;and n is 1 or
 2. 2. A process according to claim 1, wherein theacylation reaction (first stage) is carried out in the presence of aLewis acid.
 3. A process according to claim 1, wherein an acyl halide isused for the acylation reaction.
 4. A process according to claim 1,wherein the base K₂CO₃, is employed in a concentration of from 0.8 to 2mol, based on the phenol compound employed.
 5. A process according toclaim 4, wherein the base is employed in a concentration of from 0.9 to1.1 mol, based on the phenol compound employed.
 6. A process accordingto claim 1, wherein the oxidation (3^(rd) reaction stage) is carried outin the presence of percarboxylic acids.
 7. A process according to claim6, wherein the oxidation is carried out in the presence of n MCPBA(m-chloroperbenzoic acid) or peracetic acid.
 8. A process according toclaim 1, wherein the oxidation (3^(rd) reaction stage) is carried out inthe presence of a mixture of hydrogen peroxide/sulfuric acid/aceticacid.
 9. A process according to claim 1, which relates to thepreparation of compounds of the formula (1) in which R₁ and R₂ are Cl.10. A process according to claim 1, which relates to the preparation ofcompounds of the formula


11. A process according to claim 1, which relates to the preparation ofthe compounds of the formula